Bicyclic proline analogues are used in the discovery and development of peptidomimetic drugs. (A. Trabocchi et al. (2008) Amino Acids (2008) 34: 1-24). The hepatitis C virus protease inhibitors boceprevir (SCH 505034; ((1R,2S,5S)—N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide) (Malcolm et al. (2006) Antimicrob. Agents Chemother. 50(3): 1013 20), and telaprevir (VX 950; N—((S)-1-cyclohexyl-2-((S)-1-((1S,3aR,6aS)-1-((R)-3-(2-(cyclopropylamino)-2-oxoacetyl)hexanoyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxoethyl)pyrazine-2-carboxamide) (Perni et al. (2006) Antimicrob. Agents Chemother. 50(3): 899 909) are shown below:

Boceprevir and telaprevir are prepared from esters of the cis-fused bicyclic L-proline analogues (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid, respectively, which are shown below:

WO 2000/20824 and WO 2002/18369 describe numerous other hepatitis C protease inhibitors incorporating various fused bicyclic L-proline analogues corresponding to structural Formula VI.
Although methods for the synthesis of such complex molecules using the methods and tools of organic chemistry have been reported, those syntheses generally are multi-step, intricate, expensive, inefficient, processes of low overall yield.
Wu et al. (WO 2007/075790) discloses the production of the methyl ester of the bicyclic proline analogue (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid from the corresponding symmetrical (achiral) bicyclic amine of structural formula (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane, beginning with its oxidation to the corresponding racemic imine of structural formula

The racemic imine is subsequently reacted with cyanide to provide the racemic aminonitrile of the following structural formula

which is then reacted with acid and methanol to give the racemic amino acid methyl ester of the following structural formulae

Finally, these (1R,2S,5S) (undesired) and (1S,2R,5R) (desired) stereoisomeric methyl esters are separated by diastereomeric salt resolution, forming either the di-p-tolyl-D-tartaric acid salt with the former enantiomer or the di-p-tolyl-L-tartaric tartaric acid salt with the latter enantiomer.
Tanoury et al. (WO 2007/022459) disclose the synthesis of racemic (t-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid from the corresponding symmetrical (achiral) bicyclic amine by making the N-Boc derivative, and reacting it with the pyrophoric agent, sec-butyllithium in the presence of more than a stoichiometric amount of a bulky diamine chelate, then carbon dioxide, all at below −70° C. to produce the racemic N-Boc amino acids depicted below:

The (1R,2S,5S) (undesired) and (1S,2R,5R) (desired) stereoisomers of these racemic Boc-acids are then separated by diastereomeric salt resolution using single enantiomer chiral bases such as S-1-aminotetralin.
Although the desired stereoisomer of the amino acid derivative is obtained by these methods, the resolution of a mixture of enantiomers of these bicyclic proline analogues inherently involves the waste of at least one half of all of the material (e.g. raw materials, reagents, solvents, catalysts) used in the production of the racemic mixture.
Additional methods for the chemical synthesis of amino acid (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid and its esters have also been reported involving (i) anodic oxidation of N-acetyl-3-azabicyclo[3.3.0]octane (EA 00090362), and (ii) a thiazolium glide approach (Letters in Drug Design & Discovery (2005) 2(7): 497 502); J. Org. Chem. 1994, 59, 2773-8).
Methods to asymmetrically produce amino acids of structural formula (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid and esters thereof of structural Formula V from the corresponding symmetrical (achiral) bicyclic amines of structural Formula I ((1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane) that avoid the formation of racemic mixtures, and the consequent need to separate the enantiomers can be more efficient, less wasteful, and more cost-effective than the resolution-based methods described above.
Monoamine oxidase enzymes have been used to resolve and deracemize racemic chiral amines via the stereospecific oxidation of one enantiomer to the corresponding imine using oxygen. Derivatives of the flavin dependent monoamine oxidase of Aspergillus niger (MAO N) (Shilling et al. (1995) Biochim. Biophys. Acta. 1243: 529 37) have been reported as useful, in combination with non specific chemical reducing agents, for the deracemization of (d/l) α methylbenzylamine to provide enantiomerically pure (93% ee) (d) α methylbenzylamine (Alexeeva et al. (2002) Angew. Chem. Int. Ed. 41: 3177-3180). Derivatives of the flavin dependent monoamine oxidase of Aspergillus niger were also used for deracemization of (R/S)-2-phenypyrrolidine to provide enantiomerically pure (98% ee) (R)-2-phenypyrrolidine (Carr et al. (2005), ChemBioChem 6: 637 39; Gotor et al. “Enantioselective Enzymatic Desymmetrization in Organic Synthesis,” Chem. Rev. (2005) 105: 313-54).
It is desirable therefore not only to provide substantially-enantiomerically pure chiral compounds, particularly chiral amine compounds that are useful as synthetic intermediates, but also to provide efficient, scalable biocatalytic processes for their asymmetric synthesis. It is also desirable, therefore, to provide enzymes useful in those biocatalytic processes.